Diabetes is characterized by an impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patients. Underlying defects lead to a classification of diabetes into two major groups: type 1 diabetes, or insulin demanding diabetes mellitus (IDDM), which arises when patients lack .beta.-cells producing insulin in their pancreatic glands, and type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), which occurs in patients with an impaired .beta.-cell function besides a range of other abnormalities.
Type 1 diabetic patients are currently treated with insulin, while the majority of type 2 diabetic patients are treated either with agents that stimulate .beta.-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin.
Among the agents applied for stimulation of the .beta.-cell function, those acting on the ATP-dependent potassium channel of .beta.-cells are most widely used in current therapy. The so-called sulfonylureas such as tolbutamide, glibenclamide, glipizide, and gliclazide are used extensively and other agents such as AG-EE 623 ZW also acting at this molecular site are under development (AG-EE 623 ZW is a company code for (S)-(+)-2-ethoxy-4-[2-[[3-methyl-1-[2-(1piperidinyl)phenyl]butyl]-amino]-2 -oxoethyl]benzoic acid, a compound described in European patent publication No. 147,850 (to Dr. Karl Thomae GmbH)). Among the agents applied to enhance tissue sensitivity towards insulin metformin is a representative example.
Even though sulfonylureas are widely used in the treatment of NIDDM this therapy is, in most instances, not satisfactory: In a large number of NIDDM patients sulfonylureas do not suffice to normalize blood sugar levels and the patients are, therefore, at high risk for acquiring diabetic complications. Also, many patients gradually lose the ability to respond to treatment with sulfonylureas and are thus gradually forced into insulin treatment. This shift of patients from oral hypoglycaemic agents to insulin therapy is usually ascribed to exhaustion of the .beta.-cells in NIDDM patients.
Over the years, numerous attempts have therefore been made to provide novel agents which stimulate .beta.-cell function in order to offer the NIDDM patients an improved treatment. Recently, a series of peptides derived from glucagon-like peptide-1 have been considered as insulinotropic agents for therapeutic use.
Glucagon-like peptide-1, also referred to as GLP-1, is a peptide sequence found in the C-terminal portion of mammalian proglucagon. Prior to 1985, no definite biological activity of GLP-1 had been reported. However, in 1985 it was demonstrated that the amide of a fragment of GLP-1, namely GLP-1(1-36)amide, stimulates insulin release from isolated precultured rat pancreatic islets in the presence of glucose in a dose-dependent manner (Schmidt, W. E. et al. Diabetologia 28 (1985) 704-7). This finding suggests that GLP-1(1-36)amide and related peptides might be useful in the treatment of type 2 diabetes. Due to its substantially closer sequence homology to glucagon and glucosedependent insulinotropic peptide, also referred to as GIP, Schmidt et al. suggested that an even stronger glucagon- and/or GIP-like biological activity could be expected with GLP-1(7-36) than with the intact peptide. In recent years, particular interest has focused on the GLP-1 fragments GLP-1(7-37) and GLP-1(7-36)amide and analogues and functional derivatives thereof. The designation GLP-1(1-36) indicates that the peptide fragment in question comprises the amino acid residues from (and including) number 1 to (and including) number 36 when counted from the N-terminal end of the parent peptide, GLP-1. Similarly, the designation GLP-1(7-37) designates that the fragment in question comprises the amino acid residues from (and including) number 7 to (and including) number 37 when counted from the N-terminal end of the parent peptide, GLP-1. The amino acid sequence of GLP-1(7-36)amine and of GLP-1(7-37) is given in formula I: ##STR1##
which shows GLP-1(7-36)amide when X is NH.sub.2 and GLP-1(7-37) when X is Gly--OH.
That GLP-1(7-36)amide is indeed an insulinotropic agent in man has been demonstrated by Kreymann, B. et al. who infused this peptide into healthy volunteers and observed a significant rise in plasma insulin (Lancet 2 (1987) 1300-304).
The insulinotropic action of GLP-1(7-37) in diabetic as well as in nondiabetic subjects has been demonstrated by Nathan, D. M. et al. Diabetes Care 15 (1992) 270-76.
International Patent Application No. WO 87/06941 (to The General Hospital Corporation) relates to a peptide fragment which comprises GLP-1(7-37) and functional derivatives thereof and to its use as an insulinotropic agent.
International Patent Application No. 90/11296 (to The General Hospital Corporation) relates to a peptide fragment which comprises GLP-1(7-36) and functional derivatives thereof and has an insulinotropic activity which exceeds the insulinotropic activity of GLP-1(1-36) or GLP-1 (1-37) and to its use as an insulinotropic agent.
International Patent Application No. 91/11457 (to Buckley et al.) relates to effective analogs of the active GLP-1 peptides 7-34, 7-35, 7-36, and 7-37.
The effect of GLP-1(7-37) in combination with glibenclamide on insulin secretion from rat pancreatic islets was studied in vitro by Parker, J. C. et al. (Diabetes 40 (suppl. 1) (1991) 237 A). Only an additive effect of the two agents was observed.
However, to the best of the knowledge of the present inventors the surprising synergistic effect in vivo achieved by the combined use of an oral hypoglycaemic agent and a fragment of GLP-1 or an analogue or a functional derivative thereof has not previously been disclosed.